PROJECT SUMMARY/ABSTRACT Dr. Gina Sizemore began her research career in the laboratory of Dr. Dennis Slamon at the University of California, Los Angeles where she was introduced to the molecular heterogeneity of breast cancer and the burgeoning field of precision medicine. This experience led the applicant to Case Western Reserve University where she completed her doctoral studies under the guidance of Dr. Ruth Keri on the forkhead box transcription factor, FOXA1, in normal mammary gland development and luminal breast cancer. Inspired to expand her expertise to the tumor microenvironment (TME), the applicant then ensued postdoctoral training in Dr. Michael Ostrowski?s lab at the Ohio State University Comprehensive Cancer Center (OSUCCC). The OSUCCC was recently bestowed an ?exceptional? ranking by the National Cancer Institute, and provides a strong atmosphere of collaborative, high impact science that is ideal for Dr. Sizemore to train towards her ultimate goal of a tenure-track faculty position. Dr. Sizemore?s postdoctoral work has been multi-faceted with one of her four projects culminating in this application, which addresses the role of interactive PDGFR? signaling during breast cancer initiation, progression and metastasis. PDGFR? is a targetable receptor tyrosine kinase expressed in cancer stroma and perivasculature, but its role in the breast primary and metastatic TME is not understood. To address this fundamental question, a mouse model with mesenchymal-specific activation of PDGFR? was created. These mice exhibit mammary hyperplasia and upon injection with murine breast cancer cells, display increased experimental metastases only to the brain, with intracranial tumor growth that is dependent on tumor derived PDGF-B, the ligand for PDGFR?. These preliminary findings suggest PDGF-B-to- PDGFR? signaling in the brain metastatic TME promotes metastatic progression of a subset of breast cancers. To test this hypothesis, Specific aim 1 will use mouse genetic mesenchymal-specific and pericyte-specific gain-of-function as well as pharmacologic loss-of-function approaches to determine whether PDGFR? establishes a metastatic TME that potentiates tumor growth and disease progression within the brain. Specific aim 2 will assess whether PDGF-B expression affects primary tumor growth, brain metastasis and correlates with site-specific metastasis in patients. Specific aim 3 will uncover the functional mechanisms underlying how tumor-stromal PDGFR? signaling dictates pericyte and/or tumor cell adhesion and motility during breast cancer progression. Breast brain metastases occur in 10-20% of all metastatic breast cancer patients yielding only a ~20% one year-survival rate. The completion of this proposal will uncover the relevance of PDGFR? in the breast TME and metastatic niche, and assess the clinical utility of targeting this pathway. The mouse models evaluated herein are to the applicant?s knowledge the first to model the brain metastatic niche. This K22 period will allow the candidate the protected time to characterize these models, expand her expertise in neuro- oncology and the perivasculature, and provide an excellent launching point to begin her independent career.